This invention relates generally to molecular medicine and autoimmune disorders and, more specifically, to the identification of an autoantigen receptor that mediates T cell infiltration.
The immune system is a complicated network of cells and molecules that normally work to defend the body and eliminate infections caused by bacteria, viruses, and other invading microbes. If a person has an autoimmune disease, the immune system mistakenly attacks self, targeting the cells, tissues, and organs of a person's own body. A collection of immune system cells and molecules at a target site is broadly referred to as inflammation.
There are many different types of autoimmune diseases that each affect the body in different ways. For example, the autoimmune reaction is directed against the brain in multiple sclerosis and the gut in Crohn's disease. In other autoimmune diseases such as systemic lupus erythematosus, affected tissues and organs may vary among individuals with the same disease. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus.
While the incidence of most individual autoimmune diseases is rare, as a group autoimmune diseases afflict millions of Americans. Most autoimmune diseases strike women more often than men; in particular, they affect women of working age and during their childbearing years.
In a number of autoimmune diseases including, for example, Graves' disease (GD), Rheumatoid Arthritis(RA), myasthenia gravis, insulin-resistant diabetes (Type I), antibodies to cell membrane receptors lead to anti-receptor hypersensitivity reactions that alter cellular function as a result of the binding of antibody to membrane receptors, which can have a stimulatory or a blocking effect. For example, in animal models of myasthenia gravis, the production of antibodies by immunization to the acetylcholine receptor has resulted in the typical muscle fatigue and weakness noted in affected humans, where this antibody has been shown to be present in serum and on muscle membranes and, further, prevents the binding of endogenously produced acetylcholine to its receptor, thereby preventing muscle activation. Similarly, in some diabetic patients with extreme insulin resistance, antibodies to insulin receptors have been shown that prevent the binding of insulin to its receptor.
An important aspect of Graves' disease concerns the presence in most patients of detectable IgGs directed against the thyroid-stimulating hormone receptor (TSHR). These antibodies can possess stimulatory or blocking activities, and depending on which type predominates, result in either thyroid gland over- or under-activity. While the central role for these antibodies in provoking disordered thyroid hormonogenesis and gland enlargement has been established, little direct evidence has been advanced to implicate anti-TSHR Igs in the extra-thyroidal manifestations of Graves' disease. The extra-thyroidal manifestations of Graves' disease involve the infiltration of the connective tissues of the orbit and skin of the lower leg, processes referred to as thyroid-associated ophthalmopathy (TAO) and dermopathy, respectively. These extra-thyroidal processes involve tissue remodeling, including the deposition of hyaluronan, a non-sulfated glycosaminoglycan synthesized by activated fibroblasts. Orbital tissues in TAO are often dramatically inflamed. Immunocompetent cells, including CD4+ and CD8+ T cells, mast cells and B cells, infiltrate the orbital tissue, synthesize and export mediators such as cytokines, which activate fibroblasts. The temporal discordance between the onset of hyperthyroidism and development of TAO also suggests that different causative factors underlie the glandular versus the non-glandular aspects of Graves' disease. Little progress has been made into establishing the basis for TAO and as a result, current therapy is largely nonspecific and inadequate.
The identity the autoantigen that mediates the extra-thyroidal manifestations, in particular, Thyroid-associated Opthalmopathy (TAO) and dermopathy, in which the connective tissue of the orbit and shin, respectively, undergo extensive remodeling driven by recruited T-lymphocytes can provide valuable information for other autoimmune diseases that involve recognition of the same autoantigen. For Graves' disease, the mechanism through which immunocompetent cells are trafficked to affected tissues is critical to understanding and, ultimately, to developing therapies that address both the glandular as well as the non-glandular manifestations of Graves' Disease.
Thus, there exists a need for identification of an autoantigen that is recognized by endogenous immunoglobulins and mediates autoimmune responses. The present invention satisfies this need and provides related advantages as well.